Monika Edelbauer

Activity of Childhood Lupus Nephritis is Linked to Altered T Cell and Cytokine Homeostasis

PurposeStandard therapy for lupus nephritis is based on non-specific immunosuppression. We aimed to identify specific alterations in T cell and cytokine homeostasis and possible associations with disease activity in children with lupus nephritis (LN).MethodsThe phenotype of circulating T cells from children with LN and healthy controls (HC) was analyzed by flow cytometry. Intracellular expression of IL-17 and INF-γ was assessed after stimulation with anti-CD3 and anti-CD28. Serum concentrations of IP10, CCL2, TGF-β, IL-17, and IL-23 were measured by ELISA. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 update (SLEDAI-2K).ResultsChildren with active LN displayed increased frequencies of effector memory CD4+CD45RO+CCR7− and terminal differentiated CD4+CD45RA+CCR7− T cells and reduced naive CD4+CD45RA+CCR7+ T cells compared to those with inactive LN or HC. Circulating CD4+CXCR3+ and CD4+CCR2+ T cells correlated inversely with the renal SLEDAI-2K, whereas IP10 and CCL2 showed a positive correlation. Reduced CD4+Foxp3+ T cells and serum TFG-β levels in active LN were associated with high serum IL-17 and IL-23 levels and correlated inversely with the renal SLEDAI-2K (r = −0.5855, p = 0.0013 and r = −0.6246, p = 0.0005, respectively), whereas IL-17 and IL-23 correlated positively (r = 0.5516, p = 0.0029 and r = 0.6116, p = 0.0007, respectively). Expansion of Th17 and Th1/Th17 cells in children with LN was significantly greater than in HC (p = 0.0304 and p = 0.0067, respectively).ConclusionChildren with active LN display high levels of pro-inflammatory cytokines associated with an increase in effector T cells and reduction of regulatory T cells. Therapeutic regulation of the aberrant cytokine profile might specifically interrupt pathogenic mechanisms.

Akt-Dependent Enhanced Migratory Capacity of Th17 Cells from Children with Lupus Nephritis

Th17 cells infiltrate the kidneys of patients with lupus nephritis (LN) and are critical for the pathogenesis of this disease. In this study, we show that enhanced activity of Stat3 in CD4+CD45RA−Foxp3− and Foxp3low effector T cells from children with LN correlates with increased frequencies of IL-17–producing cells within these T cell populations. The levels of retinoic acid-related orphan receptor c and IL-17 mRNA are significantly higher in PBMCs from children with LN than in those from controls. Mammalian target of rapamycin inhibition by rapamycin reduces both Stat3 activation in effector T cells and the frequency of IL-17–producing T cells in lupus patients. Complement factor C5a slightly increases the expression of IL-17 and induces activation of Akt in anti-CD3–activated lupus effector T cells. Th17 cells from children with LN exhibit high Akt activity and enhanced migratory capacity. Inhibition of the Akt signaling pathway significantly decreases Th17 cell migration. These findings indicate that the Akt signaling pathway plays a significant role in the migratory activity of Th17 cells from children with LN and suggest that therapeutic modulation of the Akt activity may inhibit Th17 cell trafficking to sites of inflammation and thus suppress chronic inflammatory processes in children with LN.

The transverse musculocutaneous gracilis flap for chest wall reconstruction in male patients with Poland's syndrome.

Polands syndrome represents a congenital unilateral deformity of the breast, chest wall, and upper limb with extremely variable manifestations. In most cases, the problem is mainly cosmetic, and the reconstruction of the chest wall should use a method designed to be performed easily and to achieve minimal scarring and donor site morbidity. We describe using a transverse musculocutaneous gracilis (TMG) flap for chest wall and anterior maxillary fold reconstruction in three male patients. In two patients, only the pectoralis major muscle was missing. In the third case, the ipsilateral latissimus dorsi muscle was also absent. The indication for surgical treatment was purely cosmetic. In all patients, a free TMG flap was performed to reconstruct the anterior axillary fold and the soft tissue defect. There was no flap loss, and all three patients had a clearly improved appearance of the chest wall. In this article, we demonstrate our experience with the use of a TMG flap for chest wall reconstruction in male patients with Polands syndrome.

Enhanced Activity of Akt in Teff Cells From Children With Lupus Nephritis Is Associated With Reduced Induction of Tumor Necrosis Factor Receptor–Associated Factor 6 and Increased OX40 Expression

OBJECTIVE The breakdown of peripheral tolerance mechanisms is central to the pathogenesis of systemic lupus erythematosus (SLE). Although true Treg cells in patients with SLE exhibit intact suppressive activity, Teff cells are resistant to suppression. The underlying mechanisms are incompletely understood. This study was undertaken to examine the Akt signaling pathway and molecules that may alter its activity in T cells in lupus patients. METHODS The Akt pathway and its regulators were analyzed in Teff and Treg cells from children with lupus nephritis and controls using flow cytometry and real-time quantitative polymerase chain reaction. T cell proliferation was assessed by analysis of 5,6-carboxyfluorescein succinimidyl ester dilution. RESULTS CD4+CD45RA-FoxP3(low) and FoxP3- Teff cells from children with lupus nephritis expressed high levels of activated Akt, resulting in the down-regulation of the proapoptotic protein Bim and an enhanced proliferative response. The induction of tumor necrosis factor receptor-associated factor 6 (TRAF6) was impaired, and TRAF6 levels inversely correlated with Akt activity. Although the expression of OX40 was enhanced on Teff cells from children with lupus nephritis compared to controls, OX40 stimulation failed to significantly increase TRAF6 expression in cells from patients, in contrast to those from healthy controls, but resulted in further increased Akt activation that was reversed by blockade of OX40 signaling. Moreover, inhibition of Akt signaling markedly decreased the proliferation of Teff cells from lupus patients. CONCLUSION Our findings indicate that hyperactivation of the Akt pathway in Teff cells from children with lupus nephritis is associated with reduced induction of TRAF6 and up-regulation of OX40, which may cause Teff cell resistance to Treg cell-mediated suppression.

Use of Biomarkers in the Management of Children with Lupus

Childhood systemic lupus erythematosus (SLE) is known to have a worse prognosis than adult-onset disease, and monitoring and treatment of the disease are still a challenge. Thus, there is an urgent need for highly reliable, non-invasive biomarkers for early detection of relapses, to avoid long-term complications and to optimize the management of children with LN. Recent studies of pediatric patients have yielded novel specific biomarkers for SLE diagnosis which can be used for monitoring disease activity and response to treatment. The most promising biomarkers in juvenile-onset SLE include cell-bound complement activation products, some genomic profiles, and urinary proteins such as neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and alpha-1-acid glycoprotein. None of these might be suitable for use as a single SLE-biomarker. More likely a combination of novel biomarkers with traditionally used data, including autoantibodies and complement, might help to enhance sensitivity and specificity for early diagnosis, disease monitoring, and prediction of relapses.cp

Unilateral gynecomastia in a prepubertal boy.

We report the case of a 12-year-old Caucasian boy with an enlarged left breast without significant skin excess. According to Simon [1] this is a grade I (Fig. 1). The boy, suffering from ADHD, had been treated since the age of 4 years with methylphenidate (10 mg/day), a potent central nervous system stimulant and amphetamine derivative. At the age of 6 years, unilateral gynecomastia was diagnosed, with an ongoing progression causing an emotional burden. On physical examination, the left breast was enlarged without galactorrhea, nipple discharge, nipple retraction, lymphadenopathy, or skin changes. Palpation of the right breast did not show any conspicuous findings. Preoperative ultrasound showed diffuse nodular breast gland hypertrophy (7×5×1 cm) of low echogenity and dense stromal fibrosis with no evidence of microcalcification, or cyst formation. The boy underwent subcutaneous mastectomy through a semicircular inferior periareolar incision. (Fig. 2) Histological examination revealed a ductal and acinar breast epithelium with stroma, fibrosis, and glandular hyperplasia with no evidence of malignancy confirming the diagnosis as “true gynecomastia.” The patient had an uneventful postoperative recovery. A 6-month follow-up showed no recurrence, and the right breast was still inconspicuous. Further systematic studies are needed to analyze endocrine dysfunctions associated with methylphenidate treatment in young patients with ADHD.

Clinical Applications of the Transverse Musculocutaneous Gracilis Flap for Secondary Breast Reconstruction after Simple Mastectomy.

Background: In secondary autologous breast reconstruction, the current standard is a flap derived from the lower abdomen or the back. If these donor sites are not available because of lack of tissue, prior operations, or simply the patient’s desire to avoid these donor sites, the authors use the transverse musculocutaneous gracilis flap if feasible. Methods: The authors retrospectively evaluated only patients where secondary autologous breast reconstruction was performed with a transverse musculocutaneous gracilis flap because of the prior mentioned reasons. Indications, limitations, advantages, and technique are discussed by sharing the authors’ experience in 23 patients using 26 transverse musculocutaneous gracilis flaps. Results: No flap loss could be observed in this series. In four patients, minimal lateral skin necrosis could easily be managed by débridement and primary wound closure. In 12 cases, subsequent lipofilling was performed for a better breast shape. On average, patient satisfaction was high. Conclusions: Secondary reconstruction after simple mastectomy using the transverse musculocutaneous gracilis flap requires a little more experience than after skin-sparing mastectomy but, especially combined with later lipofilling, can lead to an optimally shaped breast in selected patients with substantial skin laxity and fat distribution at the inner thigh. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

C-Reactive Protein and Leukocytes Do Not Reliably Indicate Severity of Influenza A Infection in Childhood:

Influenza in children may mimic other infections leading to insufficient treatment. Determination of parameters that facilitate diagnosis and indicate severity would be useful to optimize treatment modalities. We prospectively screened 432 children for influenza infection. Forty-six children at the age of 4 weeks to 14 years (median, 18 months) with confirmed influenza A infection were analyzed. A clinical score of illness severity was calculated from the symptoms presented. To evaluate the dependency of the clinical score on C-reactive protein value, leukocyte count, age, and days of hospitalization, correlation and regression analyses were carried out. Neither the C-reactive protein values (median, 0.85 mg/dL; range, 0.2-18.6; r=0.14; p=0.35) nor the leukocyte counts (median, 7.95 G/L; range, 3.5-17.6; r=-0.14, p=0.34) correlated significantly with the clinical score of influenza severity. Thus, in daily clinical practice, C-reactive protein and leukocytes seem to be insufficient parameters to describe the clinical severity of influenza A infection in children.

Lower limb salvage in a 7-month-old infant using free tissue transfer

Free flap reconstruction in infants is extremely rare. A seven-and-a-half-month-old male infant sustained an extensive soft tissue defect on his left knee caused by extravasation of an intraosseous arterenol infusion. A free latissimus dorsi flap was successfully performed for soft tissue reconstruction. Indications, advantages, and outcome of the procedure are discussed.

Molecular evaluation of renal biopsies: a search for predictive and prognostic markers in lupus nephritis

Evaluation of: Reich HN, Landolt-Marticorena C, Boutros PC et al. Molecular markers of injury in kidney biopsy specimens of patients with lupus nephritis. J. Mol. Diagn. 13(2), 143–151 (2011). The therapeutic management of patients with lupus nephritis (LN) remains a major challenge. The availability of biomarkers that accurately predict renal flares, response to immunosuppressive treatment and risk of progression to end-stage renal disease would allow the more effective use of currently available immunosuppression, with less toxicity. The molecular analysis of renal biopsy samples provides direct insights into pathologic processes in LN, and constitutes a valuable approach to discover biomarkers that may be used to improve the outcome of LN patients. Reich et al. recently described a method for simultaneously detecting multiple mRNA transcripts in archived formalin-fixed renal biopsy samples. The authors identify three transcripts (EGF, MMP7 and COL1A1) that relate to pathological indices of kidney injury and function.